The use of currently available opioid analgesics is limited by major adverse side effects such as drowsiness, respiratory depression, constipation, tolerance or addiction. Following painful peripheral tissue injury and inflammation, opioid receptors on peripheral terminals of primary sensory neurons are upregulated, their G-protein coupling, signaling and recycling is enhanced, and their activation results in potent inhibition of neuronal excitability and analgesia. The augmented intracellular signaling suggests conformational alterations of opioid receptors or ligands in the inflamed environment. Systemically applied conventional opioid agonists (e.g. morphine) activate both peripheral and central opioid receptors. Agonists at central opioid receptors lead primarily to severe side effects, leaving a significant need in the field of pain treatment for compounds that work preferably selectively on peripheral receptors.
Inflammation, accompanied by tissue acidosis, is an essential component of a large group of painful syndromes (Stein, C. et al. Brain Res Rev 60, 90-113 (2009)), including arthritis, skin inflammation, inflammatory back pain, headache (certain types of neurogenic migraine), inflammatory lesions of the central and peripheral nervous system (neuropathic pain), cancer pain, disorders of the immune system (HIV/AIDS, multiple sclerosis), traumatic and postoperative pain. Currently available analgesic drugs are limited by unacceptable side effects such as the central actions of opioids (e.g. sedation, respiratory depression, nausea, addiction, tolerance), the intestinal effects of opioids (constipation, ileus), the gastrointestinal and cardiovascular effects of cyclooxygenase (COX) inhibitors (e.g. bleeding, ulcers, thrombo-embolic complications) and the adverse effects of anticonvulsants and antidepressants (e.g. sedation, ataxia, arrhythmias, coronary vasoconstriction). Therefore, there is need of development of new generations and formulations of opioids which are devoid of these side effects but retain clinical efficacy.
This can be achieved by targeting opioid receptors on peripheral terminals of dorsal root ganglion (DRG) neurons (also called nociceptors or primary sensory neurons) through the local application of exogenous, or the release of endogenous opioids within injured tissue. Moreover, a large proportion (50-100%) of the antinociceptive effects produced by systemically administered opioids can be mediated by such peripheral opioid receptors, and opioid agonists that do not readily enter the central nervous system (CNS) can have the same analgesic efficacy as conventional opioids (Stein, C. et al. Pharmacol Rev 2011;63:860-881), Craft, R. M., et al., J Pharmacol Exp Ther 1995; 275:1535-42, amongst others). In addition, peripherally acting opioids have been shown to reduce inflammation by modulating proinflammatory mediators, edema, plasma extravasation and other parameters (Stein, C. et al. Curr Pharm Design 2012, PMID: 22747536). However, despite the fact that peripherally acting opioids have been shown to reduce inflammation, leading to potential success in pain relief strategies regarding modulation of peripheral receptors, few methods have been disclosed for effectively targeting selectively peripheral opioid receptors without effects on either the gut or CNS.
Opioid pharmacology commands a huge armamentarium of non-peptidic and peptidic opioid receptor ligands. The most thoroughly studied include the alkaloid morphine, the piperidine fentanyl, and the enkephalin derivative (D-Ala2,N-MePhe4,Gly5-ol)-enkephalin (DAMGO). All of these bind to the mu-receptor, the most important receptor type for the mediation of analgesic effects in animals and humans (Zöllner, C. and Stein, C. Handbook of Experimental Pharmacology 2007; Vol. 177 Analgesia). Chemical modification of such compounds has been accomplished manifold and has produced highly selective ligands for each receptor type as well as agonists that do not enter the CNS. While the latter can induce potent antinociception without central side effects, they are still likely to activate opioid receptors in the gut (when applied orally or systemically), which commonly results in the occurrence of constipation or vomiting. Therefore, it is necessary to develop opioid receptor-ligands with a particular focus on specific activity in the environment in damaged (inflamed) tissue.
Fentanyl is a potent synthetic opioid (“narcotic”) analgesic with a rapid onset and short duration of action. It is a potent agonist at mu-opioid receptors. Historically it has been used to treat chronic and breakthrough pain and is commonly used before, during and after procedures as a pain reliever as well as an anaesthetic. However, fentanyl can exhibit significant side effects, such as nausea, vomiting, constipation, dry mouth, somnolence, confusion, hypoventilation, apnoea, tolerance and addiction, in addition to abdominal pain, headache, fatigue, weight loss, dizziness, nervousness, hallucination, anxiety, depression, flu-like symptoms, dyspepsia (indigestion), and urinary retention, which renders fentanyl in many cases unusable, especially when delivered systemically to a subject in pain.
Structural derivatives of fentanyl have been disclosed in the prior art. Maryanoff et al (Journal of Medicinal Chemistry, 25:8, 913-919) and Riley et al (U.S. Pat. No. 3,923,992) disclose methyl-fentanyl derivatives that exhibit a methyl group at the so-called “3-position” of fentanyl. The modification of fentanyl with the methyl substituent leads to enhanced binding to opioid receptors, which enables—according to the prior art—the possibility of isolation of ligand-bound opioid receptors via affinity labelling methods (Maryanoff et al) in addition to pharmaceutical use of the derivative as an analgesic (Riley et al). Furthermore, fluor-fentanyl derivatives have been disclosed in the prior art that were intended for use in studies on opioid receptors using positron emission tomography (Hwang et al, Journal of Labelled Compounds and Radiopharmaceuticals, 23:3, 277-293). The fluor-fentanyl derivatives disclosed therein exhibit an F atom attached to the phenyl ring (not adjacent to the amide group) of fentanyl. Hwang et al report a reduction in binding strength to an opioid receptor and a reduction in analgesic effect of the fluor-fentanyl derivative compared to fentanyl itself. Importantly, none of these derivatives aimed at or generated compounds that selectively bind and activate peripheral opioid receptors in inflamed (acidic) milieu, in contrast to the present application (see below).
Despite attempts at generating fentanyl derivatives that demonstrate improved binding to opioid receptors (in normal, nonacidic milieu) and associated improvements in analgesic effect, there remains a significant need in the art to develop fentanyl derivatives that do not exhibit the side effects commonly associated with fentanyl and other conventional opioid compounds (e.g. morphine). Many of these side effects are known to be associated with the effect of such compounds on the CNS.
The mechanisms underlying the peripheral antinociceptive effects of opioids have been investigated in animals and humans (Stein, C., et al., Nat Med 9, 1003-8 (2003); Pharmacol Rev 2011;63:860-881). To this end, Freund's adjuvant (CFA)-induced hind paw inflammation in rodents has been studied, in addition to the peripheral application of small, systemically inactive doses of morphine in patients undergoing surgery or suffering from chronic arthritis. In several controlled clinical studies the inventors and others have shown that intraarticular morphine produces pain relief of similar efficacy to local anesthetics or steroids without systemic or local side effects. Such effects are apparently mediated by opioid receptors localized on peripheral terminals of DRG neurons. The activation of these receptors reduces neuronal excitability, nociceptive impulse propagation and proinflammatory neuropeptide release. In particular, it has been shown that opioid agonists inhibit the TRPV1 ion channel, which is preferentially expressed in DRG neurons and is activated by the pungent compound capsaicin, protons and other stimuli. The inhibition occurs via opioid receptor-coupled Gi/o proteins and the cAMP pathway. Furthermore, it has been shown that peripherally mediated opioid anti-nociception is particularly prominent within inflamed tissue, and that its efficacy increases with the duration of the inflammatory process. Underlying mechanisms include upregulation of synthesis, peripherally directed axonal transport and G-protein coupling of opioid receptors in DRG neurons.
Importantly, pH values as low as 4-5 have been measured in painful inflammation (Reeh, P. W. & Steen, K. H., Prog Brain Res 113, 143-51 (1996), Woo, Y. C., et al., Anesthesiology 101, 468-75 (2004). This significant change in pH in inflamed tissue provides a potential mechanism according to which inflammation-specific active agents can be developed, which only exhibit an opioid receptor agonistic function in the area of damage, inflammation and/or pain. The present invention is related to the influence of an inflamed (acidic) environment on opioid receptor-ligand interactions and provides ligands that selectively activate opioid receptors in injured (acidic, low pH) tissue. The agonists provided herein have been demonstrated to exhibit analgesic activity in animal models of inflammatory pain in vivo. The compounds disclosed herein and methods of pharmaceutical application transcend traditional concepts and methods of pain treatment relating to specific activation of peripheral opioid receptors. The present invention therefore relates to the influence of an inflamed (acidic) environment on opioid receptor-ligand interactions and provides ligands that selectively activate opioid receptors in injured tissue.